A major focus of current drug research is to improve drug targeting to internal target sites, such as to solid tumors or specific organs. The objective of drug targeting is to enhance the effectiveness of the drug by concentrating it at the target site, and minimizing its effects in non-target sites. For example, where the drug is used for therapeutic purposes, such as to treat a solid tumor, drug targeting allows more effective dosing at the target site with fewer non-tumor related side effects. Similarly, where the drug agent is a radionuclide for use in radioimaging, targeting gives enhanced contrast between the target and background areas, because of reduced background levels of the radionuclide.
Radionuclides are an important group of pharmaceutical agents for which a variety of targeting strategies have been proposed. Included in this group are radioimaging compounds, such as metal chelates of .sup.111 In, .sup.67 Ga, .sup.64 Cu, .sup.99m Tc, .sup.68 Ga, .sup.62 Zn, .sup.67 Cu, .sup.197 Hg, .sup.97 Ru, .sup.57 Co, or .sup.53 Co, which are used to image internal sites, particularly solid tumors, by intravenous administration and systemic uptake of the chelates. Also included are radiotherapeutic agents, such as the metal chelates of .sup.90 Y, .sup.197 Hg or .sup.67 CU, or conjugates of other radioactive elements, such as .sup.131 I which are used in treating tumors and the like, based on localized cell destruction from ionizing radiation. A related group of pharmaceutical agents are non-radioactive metal chelates such as iron, copper or ruthenium chelates, which produce cytotoxic effects through redox mechanisms, and can also potentiate the cytotoxic action of radiation on cells.
Previously, the inventors have described several novel chelate compounds which are useful for targeting radionuclides and radiosensitizing metals to internal sites, particularly solid tumors. In general, these compounds are bifunctional chelating agents which have, as one functional group, a chelating moiety capable of forming a tight complex with a metal ion, and as a second functional group, a chemically reactive moiety, such as a nitro or amine group, through which the compound can be coupled to a targeting or other molecule (Meares, 1976; Goodwin et al, 1975, 1976, 1979).
One novel class of chelate compounds which has been developed by the inventors are various ethylenediamintetraacetic acid (EDTA) chelates of bleomycin, which is an anti-tumor antiobiotic which localizes within many types of tumors (Umezawa, Fujii). The bleomycin/EDTA compounds have been shown to give selective tumor localization of a variety of radionuclides, including .sup.57 Co and .sup.111 In, in solid tumors. One of the earliest of these compounds was prepared by alkylating purified bleomycin A.sub.2 with a reactive bifunctional compound, such as p-bromoacetamidobenzyl-EDTA (BABE-EDTA), to link the chelate to bleomycin through a sulfonium group (DeRiemer; Goodwin, 1979, 1981; Chang). A more recent compound, formed by joining a bifunctional EDTA molecule to a bleomycin-Co complex through a monodentate cobalt-sulfur coordinate bond, is described in co-owned U.S. patent application for "Bleomycin Conjugates and Methods", U.S. Pat. No. 4,758,421 issued July 19, 1988.
One of the limitations which has been observed in targeting small radionuclide compounds, such as the above bleomycin/metal chelate compounds, to a target site, such as a solid tumor, is relatively low concentration of the compound at the target site. The low drug dose at the target site is due to the rapid clearance of the compound by the kidneys, which limits the amount the compound in the bloodstream available for localization at the target site. Merely increasing the dose of the administered compound is not a practical solution, since most of the radionuclides are toxic and therefore dose-limiting.
One method for increasing the concentration of a dose-limited, but rapidly cleared, target compound is to coadminister the compound in an antibody-complexed form. Because of its relatively large size, the complex is not cleared by the kidneys, but instead, is removed slowly from the bloodstream over a several day period by the reticuloendothelial system (RES). This approach has been investigated previously by the inventors, using two monoclonal antibodies (Mabs) prepared against the bifunctional indium/chelate compound L-benzyl-EDTA-.sup.111 In (LBEDTA-In). Binding studies showed that both antibodies were specific for the indium chelate, giving K.sub.b values for the indium chelate which were at least about 20 times those of the chelates of other metals. The antibodies, when coadministered with BLEDTA-.sup.111 In, increased the whole body level of BLEDTA-.sup.111 In after 24 hours between 10-30 times, presumably by retaining the BLEDTA-In compound in a tightly bound systemic form which is cleared slowly from the bloodstream.
The increased uptake of the compound in the presence of circulating anti-compound antibodies is, however, a relatively non-specific effect, since a variety of organs which were tested for .sup.111 In levels also showed significantly increased radioactivity after 24 hours. Therefore, the advantage of the enhanced tumor uptake of the compound produced by coadministration of an antibody is partially offset by (1) higher background levels of radioactivity (or a therapeutic agent) in non-tumor organs, and (2), greater total patient exposure to the conjugate, e.g., greater radiation exposure in the case of a conjugate having a chelated radionuclide.
Although it may be possible to reduce these unwanted side effects by flushing the patient's bloodstream with a non-toxic or non-radioactive competing antigen, the improvement in terms of reduced exposure to the compound is not dramatic. Earlier studies conducted by the inventors showed, for example, that whole body BLEDTA-.sup.111 In levels are reduced only about 20% three hours after giving a flushing dose of Fe-EDTA. Further, the antibody-enhancement approach just described requires periods of at least several hours for significant target distribution effects; therefore, the method is not suited for radionuclides such as .sup.99m Tc and .sup.68 Ga which have half lives of between about one to a few hours.